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  • br Figure Effects of Wogonoside on the Expression

    2020-03-17


    Figure 4. Effects of Wogonoside on the Expression of SMO
    (A) Effect of wogonoside on SMO expression in xenograft tissue of MDA-MB-231 STA-21 in nude mice was detected by immunochemistry.
    (B) The total SMO expression in the whole lysate of MDA-MB-231 cell xenograft tissue was tested by western blot.
    (C) The total Gli1 and SMO expression in MDA-MB-231 and MDA-MB-468 cell lines was tested by western blot.
    (F) SMO ubiquitination was tested by protein immunoprecipitation assay. The comparisons were made relative to the control group and the significance of the difference is indicated as **p < 0.01.
    (Yancopoulos et al., 2000). When cultured with MDA-MB-231 CM or MDA-MB-468 CM, the expression of p-VEGFR2 in HUVECs was much higher compared with the control group (Figures S3B 
    and S3C). In summary, the inhibitory effect of wogonoside on VEGF contributes to the reduction of angiogenesis induced by TNBC cells.
    Please cite this article in press as: Huang et al., A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling, Cell Chemical Biology (2019), https://doi.org/10.1016/j.chembiol.2019.05.004
    (legend on next page)
    Please cite this article in press as: Huang et al., A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling, Cell Chemical Biology (2019), https://doi.org/10.1016/j.chembiol.2019.05.004
    DISCUSSION
    Considering that tumor growth of breast cancer depends on angiogenesis, the recent addition of angiogenesis inhibitors (i.e., bevacizumab, Avastin) to neoadjuvant chemotherapy signif-icantly improve the progression-free survival of patients with TNBC compared with chemotherapy alone (Cella et al., 2011; Robert et al., 2011; von Minckwitz et al., 2014b). Among a variety of proangiogenic factors, VEGF and the activation of its VEGFR, which specifically stimulate endothelial cell proliferation and migration during angiogenesis, have served as primary targets for antiangiogenic therapy (Potente et al., 2011). However, the existing antibody-based VEGF blockers (e.g., bevacizumab and ramucirumab) used in TNBC have undesirable side effects, and most patients develop resistance to anti-VEGF/VEGFR therapy (Giovannini et al., 2010). Hence, effective antiangiogenic agents with fewer side effects and wider application in chemotherapy are urgently needed.
    In this study, we applied a systems pharmacology methodol-ogy to identify effective therapeutic agents for treating TNBC, and wogonoside was significantly predicted to have potential to treat TNBC. Using subject matter expertise based on a com-bination of factors (Data S1), including pharmacokinetics/ pharmacodynamics assessment, novelty, and strength of the prediction, we selected wogonoside and validated it as a potential angiogenesis inhibitor in TNBC in vitro and in vivo. Spe-cifically, the inhibitory effect STA-21 of wogonoside on TNBC was subse-quently validated by attenuation of tumor growth in nude mouse models bearing transplanted MDA-MB-231 cells. To investigate the potential molecular mechanisms of wogonoside against TNBC, we further integrated drug targets of wogonoside and known TNBC genes into the breast-specific human protein-pro-tein interactome network. Network analysis prompts us to explore whether wogonoside targets the VEGF pathway (Fig-ure 2A). In line with this, we indeed observed that wogonoside inhibited the transcription and expression of VEGF rather than influencing the viability of TNBC cells, even when treated with high concentration for 24 h (Figure S1). These observations suggest that wogonoside inhibits TNBC angiogenesis rather than having direct cytotoxic effects on TNBC cells. The tube formation and rat aortic ring experiments, together with the CAM assays, all point to wogonoside inhibiting TNBC cell-induced angiogenesis in vitro. The Matrigel plug and xenograft models further indicate that wogonoside inhibits angiogenesis